Emphysema/COPD poses an ever-increasing threat to world health. It is one of the few chronic diseases in which morbidity and mortality is dramatically increasing (Global Burden of Disease Study, 2002, World Health Organization). This project evaluates autophagy and lysosome function in a disease relevant cell, the alveolar macrophage. The hypothesis is that accumulation of non-degradable particulates alters homeostatic autophagy and lysosomal clearance mechanisms in smoker's macrophages. This disruption of an important cellular housekeeping function potentially alters gene expression and immune function leading directly to smoking-induced emphysema. Knowledge gained will be used to examine relevant interventions as a means of improving quality of life for individuals impacted by emphysema. Specific Aims: The project tests whether smoking-induced defects in the autophagy/lysosomal pathway lead to decreased clearance of damaged proteins, defective degradation of harmful particulates, mitochondrial damage, altered gene expression and impaired innate immune responses. Aim 1 will evaluate the regulation of autophagy/lysosomal pathway by cigarette smoke particulates in human alveolar macrophages. The nature of the particulate matter that builds up in smoker's alveolar macrophages will be investigated using state-of-the-art facilities available in the University of Iowa, Nanotechnology Institute. Cigarette smoke extract, control particles and smoking specific particulates will be used to examine links to the autophagy/lysosome pathway. A limited number of interventions will be tested to look for reversal of the changes to the autophagy/lysosome pathway. Aim 2 will evaluate the role of cigarette smoke-induced autophagy/lysosomal dysfunction in lung injury and repair. Possible outcomes of a breakdown in the autophagy/lysosomal pathway, including mitochondrial dysfunction, altered gene expression and impaired immune responses will be evaluated. Any interventions found to be protective in Aim 1 will be tested for efficacy. If any of the interventions appear to reverse in vitro findings, they will be tested in a murine model of emphysema for their ability to slow or alter the disease process. Summary: Alveolar macrophages in cigarette smokers facilitate the development of emphysema. The role of autophagy/lysosome dysfunction in alveolar macrophage biology is a novel area of research. Understanding these processes may suggest interventions that would improve the overall health of individuals exposed to excessive particulates whether via smoking or via other environmental exposures.